The anemia of chronic disease (ACD) is one of the most common types of anemia in the elderly and a frequent cause of morbidity in these patients. Overproduction of pro-inflammatory cytokines has been previously implicated in the pathogenesis of this syndrome, but the precise molecular mechanisms that lead to ineffective erythropoiesis are not known. We have shown that the p38 Map kinase pathway is a common mediator of the effects of different myelossuppressive cytokines on normal erythropoiesis and that its activation is essential for suppression of growth of human erythroid progenitors. We have also demonstrated that pharmacological inhibition of this pathway results in enhanced erythroid colony formation from the bone marrows of patients with ACD, suggesting a key role for this signaling cascade in the pathophysiology of this syndrome. The overall goal of this grant application is to determine the precise role of the p38 pathway in the pathogenesis of the anemias of chronic disease and to identify the mechanisms by which it mediates such effects. Specific aim A is to determine the role of p38 in the generation of the effects of the pro-inflammatory cytokine tumor necrosis factor a (TNFa) and the iron-regulatory hormone hepcidin on normal erythropoiesis. Specific aim B is to define the mechanisms of activation of the p38 pathway in bone marrows from patients with ACD, and to determine whether pharmacological or molecular inhibition of different p38-isotypes enhances the growth of erythroid progenitors from ACD-bone marrows in vitro. This will include studies using a novel inhibitor of p38, SCIO-469, that is currently under clinical development for other entities. Specific aim C is to dissect the roles of specific downstream effectors of p38 in the suppression of normal erythropoiesis in ACD bone marrows. The activation of known p38-regulated kinases, such as MapKapK2, MapKapKS, Msk1, and Mnk1, will be examined in ACD bone marrows, and their contributions to the suppression of erythropoiesis will be determined. Altogether, these studies should advance our overall understanding of the pathogenesis of chronic anemias in the elderly, and may provide the basis for the future development of novel therapeutic approaches for the treatment of ACD using as targets p38 and/or its effector kinases.